President
Bush's State of the Union address last week put AIDS and HIV in the news
again with promises of more money for drugs, care and prevention. Despite
phenomenal knowledge about the virus that causes AIDS, the disease still
eludes easy treatment and scientists continue to pursue new strategies.

One strategy is an effort to prevent HIV from getting inside human cells
by removing the "doorknob" the virus uses to get in. The effort
combines three of the hottest tools in science: stem cells, gene therapy
and RNA interference. The goal is to someday modify a person's stem cells
to make them resistant to HIV and then return these cells to the body
where they can fight disease.

The premise is simple: engineer human cells that keep HIV out. Normally
HIV enters a cell and then directs the cell to make thousands of viruses
that will eventually kill the cell and move on to other cells in the body.

The scientists are trying to prevent this disaster by blocking HIV from
getting into cells at all. To get inside, the virus grabs onto a receptor
on the human cella kind of doorknob. HIV opens the door and enters
the cell.

So the scientists made human cells without the "doorknob,"
called the CCR5 receptor. Some of these cells were not infected when they
exposed the cells to the HIV virus. To engineer the cells, the researchers
inserted short pieces of RNA that disrupted cells from making the receptor.
The technique is known as RNA interference.

"The technique is highly specific and extremely potent," says
David Baltimore of the California Institute of Technology in Pasadena,
who led the research. "We're changing the cell so it's resistant
to viral infection."

The technique is being used in cultured cells and clinical trials are
still a long way off. As a next step, Baltimore is working with Irving
L. Weissman of Stanford University in California, who has pioneered new
ways to isolate stem cells.

Together with Weissman, Baltimore hopes to marry RNA interference with
stem-cell transplants to create a new therapy for patients already infected
with HIV.

A therapy might work like this: A doctor extracts stem cells from a patient
and treats these cells with RNA to remove the CCR5 receptor. These "protected"
stem cells are reintroduced into the patient's bloodstream.

Potentially, we could reengineer the body's
immune system so it's protected for life.

The "protected" cells would be healthy enough to fight infections
and would survive to create daughter cells that are also resistant to
HIV. There would be less chance the body would reject the transplant because
the stem cells are the patient's own cells.

"Potentially, we could reengineer the body's immune system so it's
protected for life," says Irvin S. Y. Chen of the University of California
in Los Angeles, who collaborated with Baltimore on the project.

Weissman cautions that it is still "way too soon" to know which
patients are right for the therapy. The technique must still be tested
in mice and then monkeys.

The inspiration for the research comes from people who never catch HIV,
despite having unprotected sex or sharing needles with infected individuals.
These people have mutations in both genes that make the CCR5 receptor,
and the virus cannot get in. Scientists have known about this phenomenon
for decades, but developing drugs that could eliminate the protein has
been slow going.

RNA interference offers a new and accurate technique to remove the receptor.
The research hinged on finding a good delivery vehicle to get the short
RNA strands into human cellsand keep them turned on.

As it turns out, the HIV virus itself was the best delivery vehicle.
The scientists used a disabled HIV virus, stripped of all its disease-causing
genes. Its only instructions are to insert the RNA package into the human
cell, a form of gene therapy.

Gene therapy is a field that has struggled to find success in a clinical
setting. The US Food and Drug Administration recently suspended a number
of gene therapy trials after children in France developed cancer during
gene therapy.

The researchers will have to confront similar issues if the research
eventually moves into a clinical setting, says Chen. For now, their work
is moving ahead.

Other researchers in the field are also using this type of gene therapy
together with RNA interference. Inder M. Verma of the Salk Institute in
La Jolla, California has used this technique to 'silence' specific genes
in mice, which then passed the silenced genes on to their offspring.

The great thing about gene therapy is that the RNA gets into a cell and
keeps on working, says Verma, who has been studying these types of disabled
viruses since the mid 1990s. He was not involved in the HIV study.

The most effective strategy against HIV would combine blocking HIV's
entry into the cell and disrupting the virus if it gets inside. The strategy
could be used in all sorts of infectious diseases, says Chen, including
Hepatitis C and Hepatitis B.

Chen and Baltimore are testing the technique in mice, before moving onto
the Rhesus monkey, which has the same CCR5 receptor as humans.